3-ethyl-3-phenylazepane derivatives having multimodal activity against pain

Abstract

The present invention relates to 3-ethyl-3-phenylazepane derivatives having dual pharmacological activity towards both the sigma (σ) receptor and the μ-opioid receptor, to processes of preparation of such compounds, to pharmaceutical compositions comprising them, and to their use in therapy, in particular for the treatment of pain.

1 - 14 . (canceled) 
     
     
         15 . A compound of Formula (I): 
       
         
           
           
               
               
           
         
         wherein 
         m is 1, 2 or 3; 
         n is 0, 1 or 2; 
         X is selected from the group consisting of —CH 2 N(R 1′ )—, —C(O)N(R 1′ )— and —CH 2 O—; 
         R 1  is selected from the group consisting of hydrogen, substituted or unsubstituted C 1-6  alkyl, substituted or unsubstituted C 2-6  alkenyl, substituted or unsubstituted C 2-6  alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heterocyclyl; 
         R 1′  is selected from the group consisting of substituted or unsubstituted C 1-6  alkyl, substituted or unsubstituted C 2-6  alkenyl, substituted or unsubstituted C 2-6  alkynyl; alternatively, when X is —CH 2 N(R 1′ )— or —C(O)N(R 1′ )—, R 1  and R 1′  taken together with the connecting N—[CH 2 ] n  atoms may form a substituted or unsubstituted heterocyclyl having up to 6 ring members;
 wherein the alkyl, alkenyl or alkynyl in R 1  or R 1′ , if substituted, is substituted with one or more substituents selected from the group consisting of —OR 3 , halogen, —CN, haloalkyl, haloalkoxy and —NR 3 R 3′″ ; 
 wherein 
 R 3  is selected from the group consisting of hydrogen, unsubstituted C 1-6  alkyl, unsubstituted C 2-6  alkenyl and unsubstituted C 2-6  alkynyl; 
 and wherein R 3′″  is selected from the group consisting of hydrogen, unsubstituted C 1-6  alkyl, unsubstituted C 2-6  alkenyl, unsubstituted C 2-6  alkynyl and -Boc; 
 
         R 2  is selected from the group consisting of hydrogen, halogen, —R 4 , —OR 4 , —NO 2 , —NR 4 R 4′″ , —NR 4 C(O)R 4′ , —NR 4 S(O) 2 R 4′ , —S(O) 2 NR 4 R 4′ , —NR 4 C(O)NR 4′ R 4″ , —SR 4 , —S(O)R 4 , —S(O) 2 R 4 , —OS(O) 2 R 4 , —CN, haloalkyl, haloalkoxy, —C(O)OR 4 , —C(O)NR 4 R 4′ , —OCH 2 CH 2 OH, —NR 4 S(O) 2 NR 4′ R 4″  and —C(CH 3 ) 2 OR 4 ; wherein
 R 4 , R 4′  and R 4″  are independently selected from the group consisting of hydrogen, unsubstituted C 1-6  alkyl, unsubstituted C 2-6  alkenyl, and unsubstituted C 2-6  alkynyl; 
 R 4′″  is selected from hydrogen, unsubstituted C 1-6  alkyl, unsubstituted C 2-6  alkenyl, unsubstituted C 2-6  alkynyl and -Boc; 
 
         optionally as a stereoisomer, including enantiomers and diastereomers, a racemate, or a mixture of at least two stereoisomers, including enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof. 
       
     
     
         16 . The compound according to  claim 15 , wherein the compound of Formula (I) is a compound of formula (I′): 
       
         
           
           
               
               
           
         
         wherein 
         m is 1, 2 or 3; 
         X is selected from the group consisting of —CH 2 N(R 1′ )—, —C(O)N(R 1′ )— and —CH 2 O—; 
         R 1  is selected from the group consisting of hydrogen, substituted or unsubstituted C 1-6  alkyl, substituted or unsubstituted C 2-6  alkenyl, substituted or unsubstituted C 2-6  alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heterocyclyl; 
         R 1′  is selected from the group consisting of substituted or unsubstituted C 1-6  alkyl, substituted or unsubstituted C 2-6  alkenyl, and substituted or unsubstituted C 2-6  alkynyl; 
         alternatively, when X is —CH 2 N(R 1′ )— or —C(O)N(R 1′ )—, R 1  and R 1′  taken together with the connecting N atom may form a substituted or unsubstituted heterocyclyl having up to 6 ring members;
 wherein the alkyl, alkenyl or alkynyl in R 1  or R 1′ , if substituted, is substituted with one or more substituents selected from the group consisting of —OR 3 , halogen, —CN, haloalkyl, haloalkoxy and —NR 3 R 3′″ ; 
 wherein 
 R 3  is selected from the group consisting of hydrogen, unsubstituted C 1-6  alkyl, unsubstituted C 2-6  alkenyl and unsubstituted C 2-6  alkynyl; 
 and wherein R 3′″  is selected from the group consisting of hydrogen, unsubstituted C 1-6  alkyl, unsubstituted C 2-6  alkenyl, unsubstituted C 2-6  alkynyl and -Boc; 
 
         R 2  is selected from the group consisting of hydrogen, halogen, —R 4 , —OR 4 , —NO 2 , —NR 4 R 4′″ , —NR 4 C(O)R 4′ , —NR 4 S(O) 2 R 4′ , —S(O) 2 NR 4 R 4′ , —NR 4 C(O)NR 4′ R 4″ , —SR 4 , —S(O)R 4 , —S(O) 2 R 4 , —OS(O) 2 R 4 , —CN, haloalkyl, haloalkoxy, —C(O)OR 4 , —C(O)NR 4 R 4′ , —OCH 2 CH 2 OH, —NR 4 S(O) 2 NR 4′ R 4″  and —C(CH 3 ) 2 OR 4 ; wherein
 R 4 , R 4′  and R 4″  are independently selected from the group consisting of hydrogen, unsubstituted C 1-6  alkyl, unsubstituted C 2-6  alkenyl, and unsubstituted C 2-6  alkynyl; 
 
         R 4′″  is selected from the group consisting of hydrogen, unsubstituted C 1-6  alkyl, unsubstituted C 2-6  alkenyl, unsubstituted C 2-6  alkynyl and -Boc. 
       
     
     
         17 . The compound according to  claim 16 , wherein when X is —CH 2 N(R 1′ )— or —C(O)N(R 1 )—, R 1  and R 1′  taken together with the connecting N atom may form a substituted or unsubstituted 6-membered heterocycyl. 
     
     
         18 . The compound according to  claim 15 , wherein R 1  is selected from the group consisting of hydrogen, substituted or unsubstituted C 1-6  alkyl, substituted or unsubstituted cycloalkyl and substituted or unsubstituted heterocyclyl. 
     
     
         19 . The compound according to  claim 18 , wherein R 1  is selected from the group consisting of hydrogen, substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted isopropyl, substituted or unsubstituted isobutyl, substituted or unsubstituted cyclopropyl and substituted or unsubstituted pyridine. 
     
     
         20 . The compound according to  claim 15 , wherein R 2  is hydrogen or —OR 4 . 
     
     
         21 . The compound according to  claim 20 , wherein R 2  is —OH or —O-methyl. 
     
     
         22 . The compound according to  claim 21 , wherein R 2  is in the meta position. 
     
     
         23 . The compound according to  claim 15 , wherein the 6-membered heterocyclyl in R 1 -R 1″  is a substituted or unsubstituted group selected from piperidine, piperazine and morpholine. 
     
     
         24 . The compound according to any one of  claim 15 , wherein when X is —CH 2 N(R 1′ )— or —C(O)N(R 1′ )— and when R 1  and R 1′  taken together with the connecting N—[CH 2 ] n  atoms or N atom form a substituted or unsubstituted 6-member heterocyclyl, —X—[CH 2 ] n —R 1  or —X—R 1  is represented by 
       
         
           
           
               
               
           
         
       
       respectively,
 with Y being selected from —O—, —N(R 1″ )— or —CH(R 1″ )— and 
 R 1″  being selected from the group consisting of hydrogen, substituted or unsubstituted C 1-6  alkyl, substituted or unsubstituted C 2-6  alkenyl, or substituted or unsubstituted C 2-6  alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heterocyclyl. 
 
     
     
         25 . The compound according to  claim 24 , wherein R 1″  is selected from the group consisting of hydrogen, unsubstituted C 1-4  alkyl, and unsubstituted aryl. 
     
     
         26 . The compound according to  claim 15 , which is selected from the group consisting of:
 3-ethyl-3-(3-methoxyphenyl)-1-(2-(4-methylpiperazin-1-yl)ethyl)azepane,   3-ethyl-3-(3-methoxyphenyl)-1-(2-(4-phenylpiperazin-1-yl)ethyl)azepane,   4-(2-(3-Ethyl-3-(3-methoxyphenyl)azepan-1-yl)ethyl)morpholine,   3-ethyl-3-(3-methoxyphenyl)-1-(2-(piperidin-1-yl)ethyl)azepane,   1-(2-ethoxyethyl)-3-ethyl-3-(3-methoxyphenyl)azepane,   3-(3-ethyl-1-(2-(4-methylpiperazin-1-yl)ethyl)azepan-3-yl)phenol,   3-(3-ethyl-1-(2-(4-phenylpiperazin-1-yl)ethyl)azepan-3-yl)phenol,   3-(3-ethyl-1-(2-morpholinoethyl)azepan-3-yl)phenol,   3-(3-ethyl-1-(2-(piperidin-1-yl)ethyl)azepan-3-yl)phenol,   3-(3-ethyl-1-(2-hydroxyethyl)azepan-3-yl)phenol,   3-(1-(2-ethoxyethyl)-3-ethylazepan-3-yl)phenol,   3-(3-ethyl-1-(2-isopropoxyethyl)azepan-3-yl)phenol,   2-(3-ethyl-3-(3-hydroxyphenyl)azepan-1-yl)-1-(piperidin-1-yl)ethanone,   3-(3-ethyl-1-(2-(pyridin-3-yloxy)ethyl)azepan-3-yl)phenol,   2-(3-ethyl-3-(3-hydroxyphenyl)azepan-1-yl)-N,N-dimethylacetamide,   2-(3-ethyl-3-(3-hydroxyphenyl)azepan-1-yl)-1-morpholinoethanone,   3-(3-ethyl-1-(2-methoxyethyl)azepan-3-yl)phenol,   3-(1-(2-cyclopropoxyethyl)-3-ethylazepan-3-yl)phenol,   3-(3-ethyl-1-(2-(2-hydroxy-2-methylpropoxy)ethyl)azepan-3-yl)phenol,   (S)-3-(1-(2-ethoxyethyl)-3-ethylazepan-3-yl)phenol,   (R)-3-(1-(2-ethoxyethyl)-3-ethylazepan-3-yl)phenol,   3-[1-(2-Ethoxyethyl)-3-ethylazepan-3-yl]aniline,   N-{3-[1-(2-Ethoxyethyl)-3-ethylazepan-3-yl}phenyl)methanesulfonamide,   N-{3-[1-(2-Ethoxyethyl)-3-ethylazepan-3-yl]phenyl}propane-2-sulfonamide,   optionally as a stereoisomer, including enantiomers and diastereomers, a racemate, or a mixture of at least two stereoisomers, including enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.   
     
     
         27 . A process for the preparation of the compound of Formula (I) according to  claim 15 , which process comprises the reduction of a compound of Formula XI 
       
         
           
           
               
               
           
         
       
       or the alkylation of a compound of Formula IX 
       
         
           
           
               
               
           
         
       
       with a compound of formula Xa 
       
         
           
           
               
               
           
         
       
       or the reductive amination of a compound of Formula IX 
       
         
           
           
               
               
           
         
       
       with a compound of formula Xb 
       
         
           
           
               
               
           
         
       
       wherein R 1 , R 2 , X, m and n are as defined in  claim 15  and L is a leaving group. 
     
     
         28 . A process for the preparation of the compound of Formula (I′) according to  claim 16 , which process comprises the reduction of a compound of Formula XI′ 
       
         
           
           
               
               
           
         
       
       or the alkylation of a compound of Formula IX 
       
         
           
           
               
               
           
         
       
       with a compound of formula Xa′ 
       
         
           
           
               
               
           
         
       
       or the reductive amination of a compound of Formula IX 
       
         
           
           
               
               
           
         
       
       with a compound of formula Xb′ 
       
         
           
           
               
               
           
         
       
       wherein R 1 , R 2 , X, m and n are as defined in  claim 16  and L is a leaving group. 
     
     
         29 . A process for the preparation of the compound of Formula (I) according to  claim 15 , employing a compound of formula II, III, IV, V, VI, VII, VIII, IX, Xa, Xa′, Xb, Xb′, Xc, Xc′, XI or XI′, 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       wherein R 1 , R 2 , X, m and n are as defined in  claim 15  and Z is chloro, bromo or iodine. 
     
     
         30 . A pharmaceutical composition which comprises the compound according to  claim 15 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant or vehicle. 
     
     
         31 . A method of treating pain in a subject in need thereof, comprising administration of an effective amount of the compound according to  claim 15 . 
     
     
         32 . The method according to  claim 15 , wherein the pain is selected from the group consisting of medium to severe pain, visceral pain, chronic pain, cancer pain, migraine, inflammatory pain, acute pain, neuropathic pain, allodynia and hyperalgesia.